Abstract
352 Background: Pancreatic cancer is one of the most aggressive types of cancer, and lack of effective treatment results in a very low 6-month survival rate. This study aims to explore the enhancement of therapeutic effect on human pancreatic cancer cell lines (AsPC-1, MiaPaCa-2 and PANC-1) via combination of triptolide (TPL),derived from the herb Tripterygium wilfordii, and 5-fluorouracil (5-FU). Methods: Cell proliferation was measured by MTT, apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-8, 9, 3 and PARP. To explore the role of nuclear factor kappaB (NF-kB) activity in pancreatic cancer cell lines, AsPC-1/IkBaM and PANC-1/IkBaM cells (NF-kB activity of AsPC-1 and PANC-1 cells was silenced by IkB-a mutation) were treated with TPL plus 5-FU. NF-kB activity was determined by electrophoretic mobility shift assay. Results: TPL demonstrated toxicity on three pancreatic cancer cell lines with the IC50 of 25-40 nM. The combination of TPL (IC30 concentration) and 5-FU enhanced the cytotoxicity significantly compared to not only 5-FU alone but also Gemcitabine (the first line drug for advanced pancreatic cancer) alone. Combination index (CI) indicated the effect of TPL plus 5-FU was highly synergistic. Furthermore, pancreatic cancer cells treated with TPL plus 5-FU exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with TPL or 5-FU or Gemcitabine alone. In the mechanism study, AsPC-1/IkBaM and PANC-1/IkBaM cells showed more resistance to enhanced apoptosis induced by TPL plus 5-FU compared to wild-type cells. It indicated the enhanced effect of TPL was related with NF-kB activity. Conclusions: 1) TPL has a potent therapeutic effect on pancreatic cancer cell lines; 2) the combination of TPL with 5-FU enhances the therapeutic effect which is more powerful than Gemcitabine in vitro, low concentration of TPL showed high synergistic effect with 5-FU; 3) the inhibitory effect of TPL plus 5-FU on pancreatic cancer is mediated by the induction of apoptosis and TPL enhanced the apoptosis via inhibition of NF-kB activity.
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